Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies

The Marfan syndrome (MFS) is a pleiotropic, autosomal dominant disorder of connective tissue with highly variable clinical manifestations including aortic dilatation and dissection, ectopia lentis, and a series of skeletal anomalies. Mutations in the gene for fibrillin-1 (FBN1) cause MFS, and at least 337 mainly unique mutations have been published to date. FBN1 mutations have been found not only in MFS but also in a range of connective tissue disorders collectively termed fibrillinopathies ranging from mild phenotypes, such as isolated ectopia lentis, to severe disorders including neonatal MFS, which generally leads to death within the first two years of life. The present article intends to provide an overview of mutations found in MFS and related disorders and to discuss potential genotype-phenotype correlations in MFS.     

足筋膜间隙综合征相关肌肉磁刺激运动诱发电位的临床研究

目的:探讨足筋膜间隙综合征患者相关肌肉的磁刺激运动诱发电位(MEP)的特征及其临床意义.方法:对21例确诊为单侧足筋膜间隙综合征患者,在双侧腘窝上缘用磁刺激坐骨神经,同心圆针电极插入双侧足部各筋膜间隙内相应的肌肉中,记录各自MEP的潜伏期及波幅变化,并计算其比值,分析该比值与足筋膜间隙综合征发生的相关性.结果:正常足部各筋膜间隙内相应的肌肉磁刺激MEP先正后负,潜伏期相对恒定,但波幅不够稳定;当间隙内压大于30mmHg时,间隙内相应肌肉MEP潜伏期明显延长,为健侧的(1.9l±0.23)倍.统计学分析显示,筋膜间隙综合征的发生与磁刺激MEP波幅比值降低之间无相关性(P＞0.05),而与相应肌肉MEP潜伏期比值的变化之间存在着明显相关性(P＜0.01).结论:磁刺激MEP作为诊断足筋膜间隙综合征的客观指标具有重要的价值.     

Renpenning syndrome in an Indian patient

Renpenning syndrome is one of the well‐characterized causes of X‐linked intellectual disability and is associated with microcephaly and various visceral malformations. Face is considered characteristic but the dysmorphism is subtle. Here we report an Indian adult with a very lean habitus, progressive atrophy of the upper back muscles, microcephaly, loss of cervical lordosis, and upper thoracic scoliosis. Using whole‐exome sequencing, a hemizygous deletion was identified in PQBP1 that leads to a frameshift and premature termination of translation. The loss of normal curvatures of cervical and upper thoracic spine due to muscular atrophy is a characteristic feature, though it may be age dependent.     

Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C‐terminal amino acid sequence

Defects in the gene encoding synaptotagmin 2 (SYT2) have been linked to a presynaptic congenital myasthenic syndrome (CMS) and motor neuropathies. However, to date only dominant forms of the disease have been described. We report here a consanguineous patient with a severe recessive form of presynaptic CMS and denervation atrophy caused by the homozygous mutation c.1191delG, p.Arg397Serfs*37 in SYT2. The affected 2‐year‐old girl had profound weakness and areflexia with moderate bulbar deficit. Repetitive nerve stimulation revealed an extreme reduction of compound muscle action potential amplitudes at rest, with a striking facilitation followed by a progressive decline at fast stimulation rates. These findings were reminiscent, but not identical to those seen in the Lambert–Eaton myasthenic syndrome. 3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle fatigue, but albuterol was ineffective. Modeling of the mutation using the rat Syt1 C2B x‐ray structure revealed that Arg397Serfs*37 disrupts a highly conserved amino acid sequence at the bottom face of the C2B domain not directly involved in calcium binding, but crucial for synaptotagmin‐SNARE interaction and exocytosis. Thus, this report describes a recessive form of synaptotagmin 2‐CMS and highlights the importance of the synaptotagmin C‐terminal on synaptic vesicle fusion and exocytosis.     

Eye tracking as an objective measure of hyperphagia in children with Prader‐Willi syndrome

This study examined sensitivity of eye tracking measures to hyperphagia severity in Prader‐Willi syndrome (PWS). Gaze data were collected in 57 children with PWS, age 3–11 years, and 47 typically developing peers at two study sites during free visual exploration of complex stimulus arrays that included images of food, animals, and household objects. Analysis of the number and duration of fixations as well as gaze perseverations revealed that food items are not exceptionally salient for children with PWS. Instead, increased attention to food in the context of other high‐interest items (e.g., animals) was associated with caregiver reports of more severe hyperphagia and more advanced nutritional phase. The study also provided preliminary evidence of possible genetic subtype and sex differences as well as demonstrated that multiple investigators in a wide range of settings can effectively implement the eye tracking protocol. The results indicate that gaze characteristics derived from eye tracking may be a promising objective marker of hyperphagia in PWS for use in research and clinical trials.     

Kabuki syndrome with midgut malrotation and hyperinsulinemic hypoglycemia: A rare co‐occurrence from Thailand

Kabuki syndrome (KS) is a rare heterogeneous phenotypic genetic syndrome, characterized by hypotonia, developmental delay and/or intellectual disability with typical facial features. It is challenging to diagnose KS in newborn and young infant. We report a Thai girl who presented with two rare co‐occurrence phenotypes, hyperinsulinemic hypoglycemia and midgut malrotation. She had not have distinctive facial dysmorphism during neonatal period. At 4 months of age, she had poor weight gain with some facial features suggestive KS. Singleton whole exome sequencing (WES) was carried out followed by Sanger sequencing of the supposed variant. The result indicated a novel de novo heterozygous KMT2D mutation, c.15364A>T (p.Lys5122*), confirming KS. Our patient revealed rare clinical manifestations from the diverse population and address the benefit of WES in establishing early diagnosis of KS before typical facial gestalt exhibited, which allows timely and appropriate management to maximize developmental achievement.     

Metabolic and cardiovascular risk factors in Klinefelter syndrome

Klinefelter syndrome (KS), which normally presents with a 47,XXY karyotype, is the most common sex chromosome disorder in males. It is also the most common genetic cause of male infertility. KS subjects are typically tall, with small and firm testes, gynecomastia, broad hips, and sparse body hair, although a less evident presentation is also possible. KS is also characterized by a high prevalence of hypogonadism, metabolic syndrome (MetS) and cardiovascular disease. The aim of this article is to systematically review metabolic and the cardiovascular risk factors in KS patients. Hypogonadism has an important role in the pathogenesis of the changes in body composition (particularly visceral obesity) and hence of insulin resistance and MetS, but the association between KS and MetS may go beyond hypogonadism alone. From childhood, KS patients may show an increase in visceral fat with a reduction in lean body mass and an increase in glucose and impaired fat metabolism. Their increased incidence of congenital anomalies, epicardial adipose tissue, and thromboembolic disease suggests they have a higher risk of cardiovascular disease. There is conflicting evidence on the effects of testosterone therapy on body composition and metabolism.     

Increased Contact Time and Strength Deficits in Runners With Exercise-Related Lower Leg Pain

ContextExercise-related lower leg pain (ERLLP) is common in runners.ObjectiveTo compare biomechanical (kinematic, kinetic, and spatiotemporal) measures obtained from wearable sensors as well as lower extremity alignment, range of motion, and strength during running between runners with and those without ERLLP.DesignCase-control study.SettingField and laboratory.Patients or Other ParticipantsOf 32 young adults who had been running regularly (>10 mi [16 km] per week) for ≥3 months, 16 had ERLLP for ≥2 weeks and 16 were healthy control participants.Main Outcome Measure(s)Both field and laboratory measures were collected at the initial visit. The laboratory measures consisted of alignment (arch height index, foot posture index, navicular drop, tibial torsion, Q-angle, and hip anteversion), range of motion (great toe, ankle, knee, and hip), and strength. Participants then completed a 1.67-mi (2.69-km) run along a predetermined route to calibrate the RunScribe devices. The RunScribe wearable sensors collected kinematic (pronation excursion and maximum pronation velocity), kinetic (impact g and braking g), and spatiotemporal (stride length, step length, contact time, stride pace, and flight ratio) measures. Participants then wore the sensors during at least 3 training runs in the next week.ResultsThe ERLLP group had a slower stride pace than the healthy group, which was accounted for as a covariate in subsequent analyses. The ERLLP group had a longer contact time during the stance phase of running (mean difference [MD] = 18.00 ± 8.27 milliseconds) and decreased stride length (MD = −0.11 ± 0.05 m) than the control group. For the clinical measures, the ERLLP group demonstrated increased range of motion for great-toe flexion (MD = 13.9 ± 4.6°) and ankle eversion (MD = 6.3 ± 2.7°) and decreased strength for ankle inversion (MD = −0.49 ± 0.23 N/kg), ankle eversion (MD = −0.57 ± 0.27 N/kg), and hip flexion (MD = −0.99 ± 0.39 N/kg).ConclusionsThe ERLLP group exhibited a longer contact time and decreased stride length during running as well as strength deficits at the ankle and hip. Gait retraining and lower extremity strengthening may be warranted as clinical interventions in runners with ERLLP.     

Pathogenesis of antiphospholipid syndrome: recent insights and emerging concepts

Introduction: Even though our understanding of the antiphospholipid syndrome (APS) has improved tremendously over the last decades, we are still not in a position to replace symptomatic anticoagulation by pathogenesis based causal treatments.

Areas covered: Recent years have provided further insights into pathogenetically relevant mechanisms. These include a differentiation of pathogenic subtypes of antiphospholipid antibodies (aPL), novel mechanisms modulating disease activity, for example, extracellular vesicles and microRNA, and novel players in pathogenesis, for example, neutrophils and neutrophil extracellular traps (NETs).

Expert commentary: It is evident that aPL induce a proinflammatory and procoagulant state and recent data suggest that different aPL species activate different signaling pathways which sometimes converge into a common cellular response. This implies that presence of more than one aPL species may disproportionally increase the risk for the major manifestations of APS, that is, thrombosis and fetal loss. Further delineation of the pathogenic mechanisms will hopefully provide clues to causal rather than symptomatic treatments of APS.     

The changing survival profile of people with Down's syndrome: implications for genetic counselling

Cohort studies have indicated that the survival of individuals with Down's syndrome has dramatically increased over the past 50 years. Early childhood survival in particular has shown major improvement, due largely to advances in cardiac surgery and in general health management. The present study was based on a continuous cohort of 1332 people with Down's syndrome in Western Australia, registered for intellectual disability services between 1953 and 2000. Their life expectancy was 58.6 years, 25% lived to 62.9 years, and the oldest living person is 73 years of age. Life expectancy for males was greater than females by 3.3 years. The substantial increase in survival across the study period means that the life expectancy of people with Down's syndrome is approaching that of the general population, but accompanied by a range of significant mid-life health problems. The findings are of relevance to all developed countries and have considerable implications in terms of the counselling information provided to families at risk of having a child with Down's syndrome.